Review Article
Evidence-based pharmacotherapy for prevention and management of cardiac allograft vasculopathy

https://doi.org/10.1016/j.pcad.2020.03.007Get rights and content

Highlights

  • CAV, mediated by a heterogenous myriad of immune and non-immune factors, is a major limiting factor of long-term survival post HT

  • Immunosuppressive therapy is a staple. mTOR inhibitors and MMF have been shown to influence the development of CAV

  • Statins’ preventive efficacy is attributed to their pleiotropic effects. Early initiation associated with improved outcomes

  • Other approaches include antioxidant vitamins, aspirin, antihypertensive agents, CMV prophylaxis, folate therapy, and G-CSF

  • Management options for established CAV are limited. Early initiation of augmented immunosuppressive therapies may be effective

Abstract

Cardiac allograft vasculopathy (CAV)—mediated by a heterogeneous myriad of immune and non-immune factors, which contribute to the progressive and diffuse thickening of the arterial allograft's tunica intima in one distinct form of CAV, and the build-up of plaque in another—is a major limiting factor of long-term survival post heart transplantation. Information on the optimal pharmacotherapeutic approaches for the prevention and management of CAV is conflicting, scattered, and inconsistent, with numerous recent studies adding to the literature. In this paper, we present a go-to clinical resource with the most updated and comprehensive information on the topic. Immunosuppressant therapy remains a staple, with mTOR inhibitors and mycophenolate mofetil (MMF) showing direct correlation with CAV prevention. More data is now available with calcineurin inhibitor (CNI) minimizing or sparing regimens. More novel approaches are being investigated for the roles of monoclonal antibodies, anti-thymocyte globulin, and bortezomib in preventing or delaying CAV. On the other hand, statins' established efficacy is attributed to lipid-lowering and lipid-independent immunomodulatory effects, with early initiation associated with improved outcomes. The choice of statin is dependent on drug-drug interactions. Other aiding approaches for the prevention of CAV include antioxidant vitamins, aspirin, vasodilators, folate therapy, and, most pertinently, cytomegalovirus prophylaxis. Larger clinical trials are needed before these options are institutionalised. For management of established CAV, early initiation of augmented immunosuppressive therapies may be effective, as well as CNI conversion to mTOR inhibitors with or without standard MMF and azathioprine therapy. Risk of acute rejection needs to be monitored during conversion. Finally, preclinical investigations highlight novel potential therapies for CAV prevention and attenuation, however robust clinical trials are needed to test their efficacy and safety.

Section snippets

Use of immunosuppressants

Immunosuppressants are an essential component of all transplant patients' regimens. They have been institutionalised for their anti-proliferative effects and prophylactic potential against acute allograft rejection. Given their antiproliferative activity, it is believed that drugs such as proliferation signalling inhibitors (sirolimus and everolimus) which inhibits mammalian target of rapamycin (mTOR) and limit proliferation of T-cells and smooth muscle cells, will be effective in preventing

Efficacy and mechanism of action

Prevention options for CAV to date remain limited. As discussed previously, development of CAV is both cholesterol dependent and independent, with dyslipidemia occurring in 60–80% of HT recipients.39 In fact, a retrospective cohort analysis in 2018 of 37 patients, found that 12 (32.4%) out of the 37 patients with low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dl developed CAV, vs 25 (15.9%) out of the 157 patients with LDL-C <100 mg/dl (P = 0.021). Time to CAV was also delayed when a

Other pharmacological approaches

Besides the use of immunosuppressants and statins for the prevention of CAV, a plethora of other unconventional pharmacological approaches have been studied. Table 4 outlines the evidence for their use.

Pharmacological management of established CAV

Despite the plethora of studies on the potential therapies for CAV prophylaxis, the treatment and management of an established diagnosis of CAV remains limited. However, progress has been made with the use of augmented immunosuppressive therapies to attenuate CAV development.

A prospective study investigated the potential reversal of early vasculopathy with the use of 3-day methylprednisolone pulse (an anti-inflammatory corticosteroid) and ATG. Out of the 76 patients who were followed up for

Preclinical investigations

Basic science investigations are leading the way in the discovery of new therapies that may have a potential in combating and preventing CAV. Several studies on animal models have reached promising conclusions for the future of CAV. Table 5 below outlines the most prominent preclinical studies related to CAV prevention and management.

These studies introduce new possibilities for the future prevention and management of CAV. Although the findings may be predictive of translational outcomes with

Conclusion and expert opinion

Cardiac allograft vasculopathy is a troublesome long-term complication in HT recipients. Due to the limited available treatment options along with the poor allograft survival prognosis, prevention continues to be a cornerstone of CAV. Antiproliferative immunosuppressive therapy with MMF is associated with only a modest decrease in intimal thickening and plaque progression, yet has been demonstrated to prolong overall survival post-HT. Although studies that have substituted everolimus for

Declaration of competing interest

MRM is a consultant for Abbott (fees paid to Brigham and Women's Hospital), Portola, Bayer, Baim Institute for Clinical Research and Triple Gene; a trial steering committee member for Medtronic and Janssen; a scientific advisory board member for Leviticus, NupulseCV and FineHeart; and a DSMB member for Mesoblast. Other authors have no pertinent disclosures.

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